Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy ...neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.
Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in ...myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A p.A131T, MAF 7.79 × 10
and c.2702T > G p.V901G, MAF 2.51 × 10
). The CSPG4
mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4
mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4
mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10
), viability (P = 8.9 × 10
), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4
(P = 0.006) and CSPG4
(P = 3.4 × 10
) mutations. Finally, in vivo diffusion tensor imaging of CSPG4
mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10
). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.
SYNJ1
has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were ...initially reported (one of Sicilian and one of Iranian origins), with the same
SYNJ1
homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same
SYNJ1
homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the
SYNJ1
homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the
SYNJ1
p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.
Abstract Introduction Triplications of SNCA , the gene encoding for α-synuclein, cause a very rare Mendelian form of early-onset parkinsonism combined with cognitive and autonomic dysfunctions. Only ...six families with SNCA triplications have been described so far, limiting our knowledge of the associated phenotype. In this study, we report clinical and genetic findings in a new Italian family with SNCA triplication. Methods The patients' phenotype was assessed by neurological examination, neuropsychological tests, and brain imaging (MRI and SPECT-DaTSCAN). For the genetic investigation, we used three independent techniques: genome-wide SNP microarrays, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification (MLPA). Results Genetic studies documented the presence of four copies of the SNCA gene in the affected family members. FISH experiments and the segregation in the family were consistent with a heterozygous triplication of the SNCA locus. The patients carrying the SNCA triplication developed early-onset parkinsonism combined with depression, behavior disturbances, sleep disorders, and cognitive decline; marked autonomic dysfunctions were not observed. Brain imaging revealed fronto-parietal atrophy and a severe striatal dopaminergic deficit. Conclusion The identification of this novel family contributes to the genetic and clinical characterization of this rare form. Our data reinforce the view that SNCA triplications cause early-onset parkinsonism, with prominent non-motor features.
Mutations in the
TARDBP
gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients ...with Parkinson’s disease (PD). A founder
TARDBP
mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with
TARDBP
mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.
Mutations in the
GBA
gene, encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the most common known genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). ...The present study aims to gain more insight into changes in lysosomal activity in different brain regions of sporadic PD and DLB patients, screened for
GBA
variants. Enzymatic activities of GCase, β-hexosaminidase, and cathepsin D were measured in the frontal cortex, putamen, and substantia nigra (SN) of a cohort of patients with advanced PD and DLB as well as age-matched non-demented controls (
n
= 15/group) using fluorometric assays. Decreased activity of GCase (− 21%) and of cathepsin D (− 15%) was found in the SN and frontal cortex of patients with PD and DLB compared to controls, respectively. Population stratification was applied based on
GBA
genotype, showing substantially lower GCase activity (~ − 40%) in
GBA
variant carriers in all regions. GCase activity was further significantly decreased in the SN of PD and DLB patients without
GBA
variants in comparison to controls without
GBA
variants. Our results show decreased GCase activity in brains of PD and DLB patients with and without
GBA
variants, most pronounced in the SN. The results of our study confirm findings from previous studies, suggesting a role for GCase in
GBA
-associated as well as sporadic PD and DLB.
Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain ...incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.
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